1999 saw the arrival of pop princesses Britney Spears and Christina Aguilera, who each received multi-platinum certificates. Simpson's label hoped for the same with her. As 1999 came to a close, Simpson released her first single, "I Wanna Love You Forever," which peaked at #3 on the Billboard Hot 100. Soon afterward her album Sweet Kisses was released. Simpson toured with boy band 98 Degrees to promote her new album. She was given a role in the music video for 98 Degrees' hit song "My Everything," playing Nick Lachey's love interest. At that time she and Lachey began dating. After dating for two years the couple cooled their relationship, stating that the "break" allowed them to concentrate on their music careers. Then on September 11, 2001, Lachey was supposed to be flying out of New York City with his group 98 Degrees. When Simpson heard of the attacks on the nation coming from the airport she immediately phoned Lachey to learn his whereabouts. After this scare the couple rekindled the relationship.

The show quickly became a pop culture phenomenon and is credited with making her a household name, even among those who did not follow pop music or MTV. “I never knew that just doing the show would give me that pedestal to step on,” Simpson told Blender magazine in a March 2004 feature.

In the summer of 2005, at age 25, Simpson made her first appearance in a motion picture as Daisy Duke in the movie remake of The Dukes of Hazzard. The film was #1 at the box office its opening weekend, although it had little or no competition (the only other new film opening that weekend was a low-budget independent film), and grossed $30.7 million on 3,785 screens. It also had an adjusted-dollar rank of #14 all-time for August releases. The film eventually collected $110.5 million world-wide, although it was much less financially successful outside the U.S.

Simpson's third film, Blonde Ambition, is set to be released July (2007). Filming is scheduled to begin in June, 2007 on a fourth movie starring Simpson, "Major Movie Star." Filming for the movie "The Witness", a spy comedy, had been scheduled for the same time but has been postponed.

Simpson received criticism from a Christian group calling itself "The Resistance", for the sexualized image she used in the music video for "These Boots are Made for Walking". In response, Simpson stated, "It didn't really surprise me because I grew up with a lot of that backlash. That's why I didn't end up going into the Christian music industry. I think that if they're really good Christians the judgment wouldn't be there."

Simpson reportedly told Jane magazine in October 2006 that she knew her marriage to Lachey was over when he refused to join her on a charity trip to Africa, even though it was on their third wedding anniversary. Questions remain over whether the trip was to celebrate the anniversary, or a PR junket guided by her father/manager, who accompanied her on that day.

The couple reportedly sold their Calabasas mansion in which Newlyweds was filmed to Malcolm in the Middle star Justin Berfield for $3.75 million.